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Marijuana use during adolescence has reached virtually every strata of society. The general population has the perception that marijuana use is safe for mature people and therefore is also safe for developing adolescents. However, both clinical and preclinical research shows that marijuana use, particularly prior to age 16, could have long-term effects on cognition, anxiety and stress-related behaviors, mood disorders and substance abuse. These effects derive from the role of the endocannabinoid system, the endogenous cannabinoid system, in the development of cortex, amygdala, hippocampus and hypothalamus during adolescence. Endocannabinoids are necessary for normal neuronal excitation and inhibition through actions at glutamate and GABA terminals. Synaptic pruning at excitatory synapses and sparing of inhibitory synapses likely results in changes in the balance of excitation/inhibition in individual neurons and within networks; processes which are necessary for normal cortical development. The interaction between prefrontal cortex (PFC), amygdala and hippocampus is responsible for emotional memory, anxiety-related behaviors and drug abuse and all utilize the endogenous cannabinoid system to maintain homeostasis. Also, endocannabinoids are required for fast and slow feedback in the normal stress response, processes which mature during adolescence. Therefore, exogenous cannabinoids, such as marijuana, have the potential to alter the course of development of each of these major systems (limbic, hypothalamic-pituitary-adrenal (HPA) axis and neocortex) if used during the critical period of brain development, adolescence. This article is part of a Special Issue entitled SI: Adolescent plasticity . [ABSTRACT FROM AUTHOR]

Recent research has demonstrated that the endogenous cannabinoid system is central to the brain's response to stress. As part of an ongoing collaboration, we sought to examine the effects of prenatal and early postnatal rearing and housing conditions on developing endocannabinoid systems. We compare brain cannabinoid receptors (CBR) in offspring of either prenatal vehicle intubated or non-treated dams (Experiment 1) or in rats derived from a vendor and shipped at weaning to a collaborating lab (Experiment 2). From postnatal day (PND) 23, all rats were either housed in isolated conditions or enriched conditions with 3 rats/cage and a variety of stimulus objects changed twice a week. All rats underwent 5 days of handling as controls for a behavior study and all rats were sacrificed at approximately PND48–50 within 2 hours of the last behavioral test. All brains were processed together for CB1 receptor binding using 3 H CP55,940 in prefrontal cortex, striatum, amygdala and hippocampus. Conditions in the two labs were as similar as possible since the two studies were intentionally designed to be comparable and contemporary. Results show that 1) comparing offspring of non-treated dams to offspring of dams receiving daily vehicle intubations, males show decreased CB1 binding in most brain regions while females only showed alterations in the hippocampus and these were increases in the offspring of the vehicle-intubated dams. 2) When comparing offspring of non-treated dams in NY with those derived from a vendor, shipped and maintained in the collaborating lab, this latter group showed reduced CB1 binding in prefrontal cortex in males and increased binding in all four brain regions in females. Therefore, overall, both prenatal handling (intubations) and being vendor-derived, shipped and maintained in a collaborating facility reduced CB1 receptors in males and increased them in females in key limbic brain regions. Effects of environmental enrichment or isolation were minor with only the prefrontal cortex showing an increase in binding in the isolated animals that were offspring of the vehicle-intubated dams. These results support the ideas that prenatal/early postnatal conditions produce different effects in males and females and override the effects of enrichment/isolation on cannabinoid receptors. Behavioral responses to cannabinoid challenges would therefore be expected to vary depending on sex, prenatal/early postnatal history and postweaning conditions of the rats. Since exogenous cannabinoids act through the CBR, the present data may provide a molecular basis for discrepant behavioral effects reported across various labs in the literature as well as sex differences seen following stress and/or manipulation of the cannabinoid system. [ABSTRACT FROM AUTHOR]

Decades of research have shown the robust behavioral, structural, and molecular effects of environmental enrichment (EE) which predominantly improves neuropathological conditions. However, systematic examination of age and sex influences in response to EE is limited. Examine the use of EE and evaluate where sex differences (or similarities) are described and whether critical developmental periods are addressed. A critical examination of review articles about EE will establish a framework for the context of the findings of EE-induced effects, improve the impact of future EE studies and improve translatability. Narrative, systematic reviews (not original reports) and meta-analyses of any animal species published during 2011 to 2021. Clinical and farming studies were excluded. Indexed review articles in Pubmed and Psychinfo. Most studies examine EE during adulthood such as following an injury or following repeated addictive drug exposure. However, in various genetic models of disease states, little attention is paid to effects of EE at different ages. Only some reviews acknowledge that sex differences exist even when the disease state under study is known to be sexually dimorphic. Identified issues include lack of systematic reporting; status of the "control group" (i.e., isolation or pair housing); the use and reporting of proper statistical analyses. Reviews have concluded that EE is most effective when administered early in life but that EE during adulthood is certainly effective. Too few review studies have compared sexes for the effects of EE to make a statement about sex differences. Overall, articles reflect a lack of integration of information on age and sex differences in response to EE. Future studies of EE should examine both sexes and consider critical periods of the lifespan in the experimental models to facilitate the adequate translation of EE as a non-pharmaceutical intervention. • A scoping review on environmental enrichment(EE), sex differences and lifespan • Reviews generally did not present interactions of age and sex in response to EE. • Inconsistent reporting on age and sex differences in response to EE was found. • Limitations of studies include: control issues, improper statistics, inadequate reporting. • In various disease models, reviews show that EE is generally beneficial. [ABSTRACT FROM AUTHOR]

Abstract: Research suggests that the use and abuse of marijuana can be especially harmful if it occurs during adolescence, a period of vast developmental changes throughout the brain. Due to the localization of cannabinoid receptors within the limbic system and the established effects of cannabinoids on emotional states and anxiety levels of rats and humans, we studied the sex- and dose-related effects of Δ9-tetrahydrocannabinol (THC, the main psychoactive component in marijuana) on behavior and anxiety during spontaneous withdrawal. Male and female Sprague Dawley rats were administered 2, 7.5 or 15mg/kg THC or vehicle from postnatal day 35–41 (approximating mid-adolescence in humans). Locomotor activity and anxiety-related behaviors were measured during drug administration and abstinence. THC caused significant dose-dependent locomotor depression during drug administration. Locomotor depression initially abated upon drug cessation, but re-emerged by the end of the abstinence period and was greater in female than male rats. We found sensitization to the locomotor-depressing effects of THC in middle- and high-dose rats and the subsequent development of tolerance in high-dose rats. The high dose of THC increased anxiety-like behaviors while the low dose decreased anxiety-like behaviors during drug administration, with females more sensitive to the anxiogenic effects of THC than males. During abstinence, females were again especially sensitive to the anxiogenic effects of THC. This study demonstrates sexually-dimorphic effects of THC on anxiety-related behaviors and locomotor activity during and after THC administration during adolescence. This information may be useful in the development of therapeutic approaches for the treatment of marijuana withdrawal in adolescents. [Copyright &y& Elsevier]

Abstract: Marijuana (Cannabis sativa) remains one of the most widely used illegal drugs, with adolescents being particularly vulnerable to its use and abuse. In spite of this, most studies are conducted in adult animals even though the effects might be quite different in adolescents. Additionally, the use of marijuana often precedes the use of other psychoactive drugs including cocaine, especially when marijuana exposure begins during early adolescence. The purpose of this study was to examine the effects of repeated Δ9-tetrahydrocannabinol (THC), the major active ingredient in marijuana, in adolescents compared to adults and to determine its subsequent effects on cocaine-stimulated activity. To this end, adolescent (postnatal day PND 34) and adult (PND 66) rats were administered 3mg/kg/day THC for 8days and locomotor activity was measured on days 1, 2, 7 and 8 after dosing. On day 12 (4days after the last dose of THC), rats were injected with escalating doses of cocaine and behavior was recorded. Results show that THC depressed locomotor activity in adult rats but not in adolescents. However, following a cocaine challenge, adolescents exposed to THC showed increased locomotor responses to cocaine compared to chronic vehicle-injected controls. This was not seen in adults. These results show that the effects of cocaine are enhanced after THC in adolescents, but not adults, and that this might account for the greater transition to cocaine after early, as opposed to later, marijuana use. [Copyright &y& Elsevier]

Abstract: Prenatal cocaine exposure produces a wide variety of effects particularly within the nervous system. While not considered a structural teratogen, preclinical studies have documented the biological effects of cocaine exposure during development; effects which to a large extent resemble those described among exposed human populations. This review evaluates the translational value of preclinical studies in terms of three factors: dose of drug administered, timing of events in brain development in the animal compared to human and pharmacokinetics of the drug in animals and humans. Cocaine''s effects on cortical development are compared across non-human primate, rabbit and rodent models. Examples of studies utilizing dose–response approaches and clinically relevant plasma drug curves are presented. And lastly, the role of environment in the manifestation of prenatal cocaine effects and published neurochemical effects of enrichment are discussed. The review concludes that there is ample evidence for the biological effects of cocaine on cortical and mesolimbic dopamine system development and that manipulation of the rearing environment can dramatically alter the manifestation of these effects including function of the mesolimbic dopamine reward system. [Copyright &y& Elsevier]

Abstract: Research suggests that use and abuse of marijuana can be especially harmful if it occurs during adolescence, a period of vast developmental changes throughout the brain. We examined the effects of 2mg/kg ∆9-tetrahydrocannabinol (THC) administered daily via intra-peritoneal injections during juvenile/early adolescence (postnatal day 22–40) or late adolescence (postnatal day 41–60) on locomotor activity, development of tolerance, and acquisition/retention of spatial avoidance in adulthood. THC caused locomotor depression in both male and female animals dosed during early adolescence but only in female animals dosed during late adolescence. Evidence of reverse tolerance to THC was seen in early adolescent animals only. In the active place avoidance test (APA), male and female animals administered THC during early adolescence made more errors on the reversal trial requiring flexibility in learning, but in animals dosed during late adolescence there were no significant sex or treatment differences. The results of the locomotor activity study indicate that females may be more sensitive to the effects of THC than males, while results of both locomotor activity and APA studies suggest that early adolescents appear to be more vulnerable to these effects than late adolescents/young adults. [ABSTRACT FROM AUTHOR]

Abstract: Cocaine alters brain function from the early days of development throughout the entire life of an individual. Since the first preclinical research on cocaine sensitization was published, sex differences in response to the drug in adult rats have been noted. With the appearance of reports on “crack babies” during the 1980s, sex differences in response to prenatal (developmental) exposure have been identified in both clinical and preclinical reports. Cocaine administered during early development in the rat produces wide-spread alterations in function which depend on the timing of drug administration as well as the sex of the animal. In males, the response patterns following postnatal days (PND) 11–20 cocaine administration (equivalent to the late prenatal period in humans) are quite similar to those seen following prenatal exposure (equivalent to the first half of pregnancy in humans). There is a general decrease in dopaminergic (DA) markers and reactivity perhaps due to the uncoupling of the D1 receptor from its second messenger system. While similar changes in D1 uncoupling are seen in females, behavioral and metabolic responses to drug challenges generally show increases in DA responsivity (except adolescents) perhaps due to the activational effects of estrogen and/or decreases in serotonin (5-HT) mediated regulation of DA function. We have found that a significant factor in the hyper-responsivity of the female is the role of the testing environment and the responses to stress which can obscure underlying neurochemical dysregulation. Whether parallel factors are operational in adult males and females is currently under investigation. [Copyright &y& Elsevier]

Repeated cocaine administration results in a progressive sensitization of behavior which typically occurs more readily in female rats than in males. Our recent studies of rats undergoing surgical procedures revealed that following anesthesia, females sensitized less than males receiving identical repeated cocaine injections. Since isoflurane acts primarily by increasing the effects of the inhibitory neurotransmitter γ-amino butyric acid (GABA) and reducing the effects of the excitatory amino acid glutamate, these amino acids may play more prominent roles in sensitization to cocaine in females than previously understood. In order to examine the effects of isoflurane on cocaine-sensitization, we administered cocaine (15mg/kg i.p) or saline to adult male and female Sprague–Dawley rats for 9 days; on day 10, half of the rats were subjected to isoflurane anesthesia and the other half did not receive anesthesia. On day 11, rats were given their last dose of either cocaine or saline. We recorded behaviors for 1h on days 1, 9 and 11. Locomotor activity and stereotyped behaviors were quantified using photo beam monitors and the scoring of video tapes, respectively. Results indicated that a single exposure to isoflurane significantly dampens the stereotypic behavior associated with repeated cocaine administration in females but not in males. They further suggest that either GABA or glutamate play more prominent roles in cocaine-sensitization behavior in females than in males. [Copyright &y& Elsevier]

Abstract: Methylphenidate (Ritalin; MPD) is one of the most commonly prescribed drugs in childhood and adolescence and many clinical studies have documented its efficacy. Due to the limitations of conducting invasive research in humans, animal models can be beneficial for studying drug effects. However, few animal studies have demonstrated the effects of methylphenidate on cognitive processes. The objective of this study was to find a dose of methylphenidate that was effective in improving performance on a spatial working memory cognitive task when administered orally to periadolescent rats. Therefore, we dosed subjects with methylphenidate at 1 or 3 mg/kg/day via gastric intubation from postnatal day 22 to 59 and assessed the effects of the drug on performance on the radial arm maze each day. To enhance performance overall, a second experiment was conducted where the subjects were moderately food restricted (to 90% of the free-feeding weight). Results of Experiment 1 show that during the first week of testing only the 3 mg/kg MPD-treated males showed improved performance (entries prior to repeated entry) when ad lib fed and housed in pairs while the same dose significantly improved performance in both males and females under conditions of food-restriction and individual housing in Experiment 2. MPD also produced a pattern of increased errors and arms entered during the first week, especially in Experiment 2. MPD increased locomotor activity when tested at postnatal day 60 in both experiments. The data suggest that 3 mg/kg oral methylphenidate improves performance on a spatial cognitive task only early in treatment in the rat. While males show improvement under conditions of both high and low motivation, females only show MPD effects when highly motivated. Hypothetically, methylphenidate may improve radial arm maze performance through increased attention and improved spatial working memory and/or alterations in locomotion, reactivity to novelty or anxiety. Regardless, the study supports the utility of the rat as a suitable model to examine the effects of low dose oral MPD. [Copyright &y& Elsevier]

Abstract: Although the oral route has traditionally been used for THC administration during the perinatal period in the rat, most studies administering THC during the postnatal period utilize intraperitoneal (ip) administration. In an effort to utilize the same route of administration in both prenatal and postnatal studies, we administered Δ-9-tetrahydrocannabinol (THC) in sesame oil by gavage during postnatal days 22–40 (equivalent to childhood to early adolescence) to male and female rats. We quantified behavior 40 min after administration in the Accuscan activity monitor on days 22, 29 and 40. In addition, we examined active and passive avoidance behaviors in treated adults. Acutely, THC had subtle effects on activity when measured during the period of drug administration and minimal effects on avoidance behaviors examined up to 140 days of age. Since several groups have found that lower doses of THC administered intraperitoneally to periadolescent rats do produce behavioral alterations, we suspect that the inordinately slow absorption of the drug via the oral route may be responsible for the paucity of significant findings in our study. Therefore, oral administration of THC, particularly under conditions of mild food deprivation, may lead to sub-psychoactive concentrations of the drug within the brain. [Copyright &y& Elsevier]

Abstract: Clinical and animal data point toward deficits in attention and arousal after prenatal cocaine exposure. Since methylphenidate (MPD) is widely used to treat attention disorders, we wanted to determine whether prenatal cocaine (PC) exposure affects the behavioral response to MPD in young rats of both sexes. Pregnant dams received 60 mg/kg of cocaine or vehicle from gestational days 8–22 by intragastric intubations. After delivery, litters were culled to 10 (5 males, 5 females) and fostered. On a single day between PND 41–44 locomotion was recorded in a Plexiglas box within an Accuscan activity monitor after receiving a single injection of 10 mg/kg intraperitoneally of MPD or saline. Rats were also videotaped for analysis of stereotyped behavior. Results showed that MPD administration enhanced locomotion compared to saline injected groups. PC exposure in male rats did not have any effect on the locomotor response to MPD compared to prenatal controls. However, PC-exposed males showed a lower amount of time spent in low intensity stereotypy compared to prenatal control males and both groups of females that received MPD. PC exposure in female rats that received MPD dampened the locomotor response compared to prenatal control females that also received MPD. In conclusion PC exposure dampens the behavioral response to MPD differentially in males and females with an apparent selectivity of locomotion in females and stereotyped behavior in males. [Copyright &y& Elsevier]

Background: Marijuana (Cannabis sativa) is the illicit drug most used by pregnant women, and behavioral and cognitive impairments have been documented in cannabis-exposed offspring. Despite the extensive use of marijuana, very limited information exists as to the consequences of prenatal cannabis exposure on the developing human brain. Methods: We optimized an in situ hybridization histochemistry technique to visualize mRNA expression in midgestation (weeks 18–22) human fetal specimens from mothers with and without documented evidence of cannabis use during pregnancy. The cannabinoid receptor type 1 (CB1) and major dopamine receptor subtypes, D1 and D2, were examined in the striatum and mesocorticolimbic structures (amygdala and hippocampus). Results: Adjusting for various covariates, we found a specific reduction, particularly in male fetuses, of the D2 mRNA expression levels in the amygdala basal nucleus in association with maternal marijuana use. The reduction was positively correlated with the amount of maternal marijuana intake during pregnancy. No significant cannabis-related alterations were detected in the hippocampus or caudal striatum for the D2, D1, and CB1 mRNA levels, although alcohol showed significant contribution to striatal D1/D2 expression. Conclusions: These human fetal findings suggest that in utero cannabis exposure may impair distinct mesocorticolimbic neural systems that regulate emotional behavior. [Copyright &y& Elsevier]

This study examined glucose metabolic rates following dopamine D1 agonist challenge in adult male rats pretreated with cocaine during postnatal days 11–20. Water-pretreated control rats showed a reliable decrease in glucose metabolism of rostral mesolimbic structures when challenged with SKF 82958 while cocaine-pretreated males did not. These data support the notion that cocaine exposure during the preweaning period dampens D1 receptor-mediated function and that the mesolimbic system exhibits a selective vulnerability to early cocaine exposure. [Copyright &y& Elsevier]

Adolescence is a life stage when sex differences, including behavioral sex differences, become dramatically apparent. [3] presented sex differences in response to stress during prenatal and early postnatal life in the rat, while [10] detailed the sexually-dimorphic responses to gestational stress in infants. The paper by [8] began to address potential mechanisms, whereby the toxicant produced sex-dependent effects in the gene expression of neuroimmune function and this was found to vary in selected brain regions differentially by sex. [Extracted from the article]

Sex differences in both the endocannabinoid system and stress responses have been established for decades. While there is ample evidence that the sexes respond differently to stress and that the endocannabinoid system is involved in this response, what is less clear is whether the endocannabinoid system mediates this response to stress differently in both sexes. Also, do the sexes respond similarly to exogenous cannabinoids (CBs) following stress? Can the administration of exogenous CBs normalize the effects of stress and if so, does this happen similarly in male and female subjects? This review will attempt to delineate the stress induced neurochemical alterations in the endocannabinoid system and the resulting behavioral changes across periods of development: prenatal, early neonatal or adolescent in males and females. Within this frame work, we will then examine the neurochemical and behavioral effects of exogenous CBs and illustrate that the response to CBs is determined by the stress history of the animal. The theoretical framework for this endeavor relates to the established effects of adverse childhood experiences (ACE) in increasing substance abuse, depression and anxiety and the possibility that individuals with high ACE scores may consume cannabinoids to "self-medicate". Overall, we see that while there are instances where exogenous cannabinoids "normalize" the adverse effects produced by early stress, this normalization does not occur in all animal models with any sort of consistency. The most compelling report where CB administration appears to normalize behaviors altered by early stress, shows minimal differences between the sexes (Alteba et al., 2016). This is in stark contrast to the majority of studies on early stress and the endocannabinoid system where both sexes are included and show quite divergent, in fact opposite, effects in males and females. Frequently there is a disconnect between neurochemical changes and behavioral changes and often, exogenous CBs have greater effects in stressed animals compared to non-stressed controls. This report as well as others reviewed here do support the concept that the effects of exogenous CBs are different in individuals experiencing early stress and that these differences are not equal in males and females. However, due to the wide variety of stressors used and the range of ages when the stress is applied, additional careful studies are warranted to fully understand the interactive effects of stress and the endocannabinoid system in males and females. In general, the findings do not support the statement that CB self-administration is an effective treatment for the adverse behavioral effects of early maltreatment in either males or females. Certainly this review should draw the attention of clinicians working with children, adolescents and adults exposed to early trauma and provide some perspective on the dysregulation of the endocannabinoid system in the response to trauma, the complex actions of exogenous CBs based on stress history and the unique effects of these factors in men and women. • Sex differences in the response of the endocannabinoid system to early life stress. • The sexes do not respond similarly to exogenous cannabinoids following stress. • Exogenous cannabinoids can normalize the effects of stress in a few cases. [ABSTRACT FROM AUTHOR]

Adolescence is a period of dramatic neural reorganization creating a period of vulnerability and the possibility for the development of psychopathology. The maturation of various neural circuits during adolescence depends, to a large degree, on one's experiences both physical and psychosocial. This occurs through a process of plasticity which is the structural and functional adaptation of the nervous system in response to environmental demands, physiological changes and experiences. During adolescence, this adaptation proceeds upon a backdrop of structural and functional alterations imparted by genetic and epigenetic factors and experiences both prior to birth and during the postnatal period. Plasticity entails an altering of connections between neurons through long-term potentiation (LTP) (which alters synaptic efficiency), synaptogenesis, axonal sprouting, dendritic remodeling, neurogenesis and recruitment (Skaper et al., 2017). Although most empirical evidence for plasticity derives from studies of the sensory systems, recent studies have suggested that during adolescence, social, emotional, and cognitive experiences alter the structure and function of the networks subserving these domains of behavior. Each of these neural networks exhibits heightened vulnerability to experience-dependent plasticity during the sensitive periods which occur in different circuits and different brain regions at specific periods of development. This report will summarize some examples of adaptation which occur during adolescence and some evidence that the adolescent brain responds differently to stimuli compared to adults and children. This symposium, "Experience during adolescence shapes brain development: from synapses and networks to normal and pathological behavior" occurred during the Developmental Neurotoxicology Society/Teratology Society Annual Meeting in Clearwater Florida, June 2018. The sections will describe the maturation of the brain during adolescence as studied using imaging technologies, illustrate how plasticity shapes the structure of the brain using examples of pathological conditions such as Tourette's' syndrome and attention deficit hyperactivity disorder, and a review of the key molecular systems involved in this plasticity and how some commonly abused substances alter brain development. The role of stimulants used in the treatment of attention deficit hyperactivity disorder (ADHD) in the plasticity of the reward circuit is then described. Lastly, clinical data promoting an understanding of peer-influences on risky behavior in adolescents provides evidence for the complexity of the roles that peers play in decision making, a phenomenon different from that in the adult. Imaging studies have revealed that activation of the social network by the presence of peers at times of decision making is unique in the adolescent. Since normal brain development relies on experiences which alter the functional and structural connections between cells within circuits and networks to ultimately alter behavior, readers can be made aware of the myriad of ways normal developmental processes can be hijacked. The vulnerability of developing adolescent brain places the adolescent at risk for the development of a life time of abnormal behaviors and mental disorders. • Symposium within the Developmental Neurotoxicology/ Teratology Society Annual Meeting, Clearwater Florida, June 2018 • Effects of environment and experiences on adolescent brain development are presented • Plasticity resulting from endogenous or exogenous activation of circuits is illustrated • The importance of peers and the development of the social brain are discussed. [ABSTRACT FROM AUTHOR]

Abstract: Prenatal cocaine exposure is associated with abnormal arousal and attention in children. Since methylphenidate (MPD) is widely used to treat attention disorders, we wanted to determine whether prenatal cocaine exposure affects brain function in response to MPD as measured by glucose metabolism in a rodent model. Pregnant rats received 60mg/kg cocaine or vehicle from gestational days 8–22 by intragastric intubation. On a single day between postnatal days 41–45, offspring received 10mg/kgi.p. of MPD or saline. After 15min, the quantified 2-deoxyglucose (2DG) method was carried out in freely behaving animals. Seventy nine brain regions were assessed but we focused on functional units such as the mesolimbic and motor circuits which were analyzed using mixed linear models. MPD increased glucose metabolism in most brain regions from 15% to 30% over saline regardless of the prenatal treatment. Prenatal cocaine produced insignificant effects on the rates of brain glucose metabolism overall but produced a reduced response to MPD in the nucleus accumbens in a rostral/caudal gradient compared to control. In addition, correlations of rates of metabolism in the mesolimbic and nigrostriatal systems with the amount of MPD-induced behavior (stereotypy and locomotion) show that prenatal cocaine alters the relationship between regional metabolism and behavior in sex-specific ways. In summary, prenatal cocaine has minimal effects on brain metabolic activity even under drug challenge conditions but has a major impact on the relationship between brain metabolism and behavior. [Copyright &y& Elsevier]

Abstract: The effect of cocaine exposure during early postnatal ages on coupling of dopamine (DA) D1- and D2-like receptors to their respective Gs/olf and Gi was examined in striatum and medial frontal cortex (MFC). Sprague–Dawley rats were subcutaneously injected with either 50mg/kg cocaine or vehicle during postnatal day (PnD) 11–20 and dopaminergic D1- and D2-like receptor signaling was evaluated at PnD 60. Results showed that cocaine exposure did not affect the magnitude of both DA D1- and D2-like receptor coupling to their respective Gs/olf and Gi in striatum. However, in the medial frontal cortex, the basal and the DA D1-like receptor and Gs association were reduced in cocaine-exposed brains. However, there was no change in basal or DA D2-like receptor-Gi linkage in medial frontal cortex. Since frontal cortex plays a critical role in regulating cognition and working memory, disruption of DA-modulated circuits or alteration of dopaminergic activity resulting from postnatal cocaine exposure may result in abnormal responses to environmental challenges leading to long-term behavioral changes. [Copyright &y& Elsevier]

Abstract: The objective of this study was to determine if prenatal cocaine affects the levels of prodynorphin and proenkephalin mRNA in male and female adolescent rats. Pregnant dams received cocaine or vehicle from gestational days 8–22 and upon delivery, the pups were fostered. At postnatal days 42–44, pups were killed and brains removed and frozen. Sections of striatum and nucleus accumbens were processed for prodynorphin and proenkephalin mRNA expression. Prenatal cocaine did not affect the expression of proenkephalin mRNA, but males showed higher expression than females. However, prodynorphin mRNA was lower in female rats exposed to cocaine compared to controls. Prenatal cocaine appears to have unique effects on neuropeptides during adolescence. [Copyright &y& Elsevier]

Abstract: The present study was designed to assess the dopaminergic and serotonergic contributions of the acoustic startle response (ASR) and the tactile startle response (TSR) in adult rats that had been perinatally exposed to AZT (azidothymidine, zidovudine; an antiretroviral agent). Each dam was randomly assigned to a treatment group: non-treated, AZT0, 100 or 150 mg/kg. Once daily gastric intubation began prenatally on gestational day (G) 19 and continued to G22 and then the pups were intubated between postnatal day (PND) 2–20. On PND60, animals were tested for responses to both acoustic and tactile stimuli following a challenge of vehicle, 0.25 or 0.5 mg/kg 8-OH-DPAT, a 5-HT1A agonist, or 0.75 or 2.0 mg/kg apomorphine (APO, a dopaminergic agonist) IP. Both DPAT and APO increased startle magnitude as expected. Additionally, perinatal AZT exposure enhanced startle responses following both DPAT and APO, an effect not due to perinatal handling or intubation. Similarly, perinatal AZT increased tactile responses following drug challenge in a gender-specific manner. Perinatal AZT also prolonged startle latencies, a change which may indicate that perinatal AZT alters conduction velocity. Therefore, the administration of AZT during the perinatal period results in long-term functional alterations within the startle reflex pathways. [Copyright &y& Elsevier]

Developmental cocaine exposure produces long-term alterations in function of many neuronal circuits. This study examined glucose metabolic rates following repeated amphetamine administration in adult male and female rats pretreated with cocaine during postnatal days (PND) 11–20. PND11–20 cocaine increased the response to amphetamine in many components of the motor system and the dorsal caudate–putamen, in particular, and decreased the metabolic response in the hypothalamus. While amphetamine alone produced widespread increases in metabolism, there were no cocaine-related effects in the mesolimbic, limbic or sensory structures. These data suggest that a brief cocaine exposure during development can alter ontogeny and result in abnormal neuronal responses to repeated psychostimulant administration in adulthood. [Copyright &y& Elsevier]

AZT (azidothymidine, zidovudine, ZDV) has become the standard medication to prevent the transmission of the human immunodeficiency virus from mother to fetus. The present study was designed to assess the acoustic startle response (ASR) in adult rats that had been perinatally exposed to AZT. Each litter was randomly assigned to a treatment group: nontreated, AZT 0, 50, 100 or 150 mg/kg. Once daily gastric intubation began prenatally between gestational day (G) 19 and 22 and then continued postnatally between postnatal day (PND) 2 and 20. Between PND75 and PND80, animals were tested for habituation to the acoustic stimuli and prepulse inhibition following a challenge of either saline or 1.0 mg/kg amphetamine (AMP) intraperitoneally. Amphetamine increased ASR and startle latencies throughout the session. The AZT100 dose increased ASR habituation. AZT treatment did not affect prepulse inhibition. Females treated with AZT150 continued to show high ASRs at the end of the startle session. AZT-treated animals showed a dose-dependent increase in peak latency, suggesting a possible abnormal conduction velocity. These effects are independent of handling and intubation effects. Therefore, perinatal AZT treatment results in long-term changes within the primary acoustic startle pathway. [Copyright &y& Elsevier]

Adolescents who use marijuana are more likely to exhibit anxiety, depression, and other mood disorders, including psychotic-like symptoms. Additionally, the age at onset of use and the stress history of the individual can affect responses to cannabis. To examine the effect of early life experience on adolescent Δ-9-tetrahydrocannabinol (THC) exposure, we exposed adolescent (postnatal day (P) 29–38) male and female rats, either shipped from a supplier or born in our vivarium, to once daily injections of 3 mg/kg THC. Our findings suggest that males are more sensitive to the anxiolytic and antidepressant effects of THC, as measured by the elevated plus maze (EPM) and forced swim test (FST), respectively, than females. Exposure to the FST increased plasma corticosterone levels, regardless of drug treatment or origin and females had higher levels than males overall. Shipping increased THC responses in females (acoustic startle habituation) and in males (latency to immobility in FST). No significant effects of THC or shipping on pre-pulse inhibition were observed. Due to differences in timing of puberty in males and females during the P29–38 period of THC treatment, we also dosed female rats between P21–30 (pre-puberty) and male rats between P39–48 (puberty). Pre-pubertal animals showed reductions in anxiety on the EPM, an effect that was not seen in animals treated during puberty. These results suggest that both sexes are more susceptible to changes in emotional behavior when THC exposure occurs just prior to the onset of puberty. Within the animals dosed from P29–38, THC increased cannabinoid receptor 1 (CB1R) mRNA expression and tended to decrease CP55,940 stimulated [ 35 S]GTPγS binding in the central amygdala only of females. Therefore, early stress enhances THC responses in males (in FST) and females (ASR habituation), THC alters CB1R expression and function in females only and prepubescent rats are generally more responsive to THC than pubertal rats. In summary, THC and stress interact with the developing endocannabinoid system in a sex specific manner during the peri-pubertal period. [ABSTRACT FROM AUTHOR]

Marijuana use by adolescents has been on the rise since the early 1990s. With recent legalization and decriminalization acts passed, cannabinoid exposure in adolescents will undoubtedly increase. Human studies are limited in their ability to examine underlying changes in brain biochemistry making rodent models valuable. Studies in adult and adolescent animals show region and sex specific downregulation of the cannabinoid 1 (CB1) receptor following chronic cannabinoid treatment. However, although sex-dependent changes in behavior have been observed during the drug abstinence period following adolescent cannabinoid exposure, little is known about CB1 receptor expression during this critical time. In order to characterize CB1 receptor expression following chronic adolescent Δ-9-tetrahydrocannabinol (THC) exposure, we used [ 3 H] CP55,940 binding to assess CB1 receptor expression in the dentate gyrus and areas CA1, CA2, and CA3 of the hippocampus in both male and female adolescent rats at both 24 h and 2 weeks post chronic THC treatment. Consistent with other reported findings, we found downregulation of the CB1 receptor in the hippocampal formation at 24 h post treatment. While this downregulation persisted in both sexes following two weeks of abstinence in the CA2 region, in females, this downregulation also persisted in areas CA1 and CA3. Expression in the dentate gyrus returned to the normal range by two weeks. These data suggest that selective regions of the hippocampus show persistent reductions in CB1 receptor expression and that these reductions are more widespread in female compared to male adolescents. [ABSTRACT FROM AUTHOR]

The mean age of first voluntary tobacco inhalation is 12.3 years (DiFranza et al., 2004). 60% of smokers start smoking before the age of 14 and 90% are dependent before reaching the age of 19. Females are typically more sensitive to nicotine than males yet few studies examine the effects of nicotine on the reward systems in pre-adolescent female subjects. This study utilized the single trial conditioned place preference (CPP) test in very young (postnatal day 25–27) rats of both sexes. Latent effects on anxiety and amphetamine response were determined 5 and 7 days following a second nicotine exposure. Results show that 0.05 mg/kg nicotine induced CPP in females following a single trial while both sexes showed CPP following the 0.5 mg/kg dose. Five days later, rats dosed with 0.05 mg/kg show increased time on the open arm of the elevated plus maze, an anxiolytic response. While baseline activity was increased in nicotine-exposed males 7 days following dosing, amphetamine response was not affected by the treatments in either sex. Therefore, our data suggest that young females are more sensitive to nicotine reward than males supporting a heightened sensitivity of the mesolimbic dopamine system in very young females. However, alterations in baseline activity were only seen in males suggesting that different components of the system are affected by nicotine in each sex. An anxiolytic response to nicotine 5 days after dosing may suggest that this very young age group is uniquely affected by this very low nicotine dose. Clearly, nicotine has substantial acute and lasting effects during pre-adolescence at doses substantially lower than seen at older ages as reported by others. These effects, which could potentially result from cigarette or e-cigarette smoking by 11–12 year old children , focus attention on the vulnerability of this age group to nicotine. [ABSTRACT FROM AUTHOR]

Abstract: Research suggests that not only is marijuana use prevalent among women of reproductive age, but a significant number of women continue to use marijuana and its derivatives throughout pregnancy. Many studies have shown, in both humans and animals, that marijuana exposure during adolescence and adulthood is detrimental to normal cognition and memory. In this study, we examined the effects of daily intravenous injections of 0.15mg/kg Δ9-tetrahydrocannabinol (THC), given to pregnant dams throughout gestation, on cognitive function in the offspring. Offspring were exposed to three tests: a passive avoidance test at postnatal day (PND) 22, an active place avoidance test at PND 45, and an attention task at PND 60, which assessed learning and long-term memory, spatial working memory and prediction, and attention, respectively. Other offspring were also given a 1mg/kg amphetamine challenge at PND 60. Passive avoidance testing showed that prenatal THC had no effect on acquisition but interfered with consolidation during retention testing. The active place avoidance task showed no treatment-related effects on acquisition but a significant treatment effect was observed in reversal performance in males. The attention task showed that a smaller percentage of THC-exposed rats completed the test, although the failure rate of both groups was quite high. Finally, THC exposed animals, both male and female, showed a dampened locomotor response to amphetamine, but females were more active than males overall. These results suggest that prenatal THC exposure has effects on certain aspects of cognitive function in rats from weaning to adulthood. These effects suggest that prenatal marijuana exposure could also alter cognitive function in humans and therefore have an impact on school performance and dampen responses to psychostimulants as well. [Copyright &y& Elsevier]

Background: Prenatal cannabis exposure has been linked to addiction vulnerability, but the neurobiology underlying this risk is unknown. Methods: Striatal dopamine and opioid-related genes were studied in human fetal subjects exposed to cannabis (as well as cigarettes and alcohol). Cannabis-related gene disturbances observed in the human fetus were subsequently characterized with an animal model of prenatal Δ-9-tetrahydrocannabinol (THC) (.15 mg/kg) exposure. Results: Prenatal cannabis exposure decreased dopamine receptor D2 (DRD2) messenger RNA expression in the human ventral striatum (nucleus accumbens [NAc]), a key brain reward region. No significant alterations were observed for the other genes in cannabis-exposed subjects. Maternal cigarette use was associated with reduced NAc prodynorphin messenger RNA expression, and alcohol exposure induced broad alterations primarily in the dorsal striatum of most genes. To explore the mechanisms underlying the cannabis-associated disturbances, we exposed pregnant rats to THC and examined the epigenetic regulation of the NAc Drd2 gene in their offspring at postnatal day 2, comparable to the human fetal period studied, and in adulthood. Chromatin immunoprecipitation of the adult NAc revealed increased 2meH3K9 repressive mark and decreased 3meH3K4 and RNA polymerase II at the Drd2 gene locus in the THC-exposed offspring. Decreased Drd2 expression was accompanied by reduced dopamine D2 receptor (D2R) binding sites and increased sensitivity to opiate reward in adulthood. Conclusions: These data suggest that maternal cannabis use alters developmental regulation of mesolimbic D2R in offspring through epigenetic mechanisms that regulate histone lysine methylation, and the ensuing reduction of D2R might contribute to addiction vulnerability later in life. [ABSTRACT FROM AUTHOR]

Abstract: Lactate uses an unknown mechanism to induce panic attacks in people and panic-like symptoms in rodents. We tested whether intraperitoneal (IP) lactate injections act peripherally or centrally to induce panic-like symptoms in rats by examining whether IP lactate directly affects the CNS. In Long-Evans rats, IP lactate (2mmol/kg) injection increased lactate levels in the plasma and the cerebrospinal fluid. IP lactate also induced tachycardia and behavioral freezing suggesting the production of panic-like behavior. To enter intermediate metabolism, lactate is oxidized by lactate dehydrogenase (LDH) to pyruvate with co-reduction of NAD+ to NADH. Therefore, we measured the ratio of NADH/NAD+ to test whether IP lactate altered lactate metabolism in the CNS. Lactate metabolism was studied in the hippocampus, a brain region believed to contribute to panic-like symptoms. IP lactate injection lowered the ratio of NADH/NAD+ without altering the total amount of NADH and NAD+ suggesting oxidation of hippocampal redox state. Lactate oxidized hippocampal redox since intrahippocampal injection of the LDH inhibitor, oxamate (50mM) prevented the oxidation of NADH/NAD+ by IP lactate. In addition to oxidizing hippocampal redox, IP lactate rapidly increased the firing rate of hippocampal neurons. Similar IP pyruvate injections had no effect. Neural discharge also increased following intrahippocampal lactate injection suggesting that increased discharge was a direct action of lactate on the hippocampus. These studies show that oxidation of brain redox and increased hippocampal firing are direct actions of lactate on the CNS that may contribute to the production of lactate-induced panic. [Copyright &y& Elsevier]

Abstract: In the traditional [14C] deoxyglucose (2DG) method for the measurement of local cerebral glucose utilization (LCGU), blood samples are collected from the femoral artery. However, the placement of a femoral catheter can affect locomotor activity of the animal. We wanted to develop a new technique for blood sampling that would not interfere with the ongoing behavior. Therefore, the present report establishes a method of collecting blood samples for the 2DG method through the jugular vein. To calibrate this method, catheters were inserted in both the femoral artery and jugular vein of adult male Sprague Dawley rats. The next day, rats were injected with 2DG (125μCi/kg) through the jugular vein. To quantify 14C in plasma, the standard method of blood collection was used for the femoral artery while syringes were used to extract blood samples from the jugular vein. We calculated the integrated specific activity of the plasma and final tissue 2DG concentrations based on Sokoloff''s original equation using blood samples derived from both vessels. LCGU determined in selected brain regions was equivalent using both sampling methods. In conclusion, sampling from the jugular vein is appropriate for the quantified 2DG method and does not disrupt locomotor activity of the rat. [Copyright &y& Elsevier]

Response variability across the lifespan is an important consideration in toxicology and risk assessment, and the toxic effects of drugs and chemicals during adolescence need more research. This paper summarizes a workshop presented in March 2019, at the Society of Toxicology Annual Meeting in Baltimore, Maryland, that brought together experts in research on drug dependence and toxicity related to nicotine, cannabis, cocaine, and other illicit drugs during adolescence. The goal of the workshop was to address the following issues: (1) Do the effects of adolescent exposure differ from the same exposure in adults? (2) Are there unique biological markers of adolescent brain development? If so, what are they and how reliable are they? (3) Since multiple factors influence substance use disorder, can we disentangle risk factors for abuse and/or toxicity? What are the underlying biological susceptibilities that lead to dependence and neurotoxicity? What are the social, psychosocial and environmental factors that contribute to abuse susceptibilities? This paper reviews drug policy and national trends in adolescent substance use; the public health consequences of e-cigarettes; rat models of adolescent-onset nicotine self-administration and persisting effects of gestational nicotine; sex-dependent effects of delta-9-tetrahydrocannabinol on adolescent brain-behavior relationships; and translational approaches for identifying adolescent risk factors for transition to drug dependence. There is strong evidence that drug exposure prior to adulthood has longer lasting effects on behavior and the underlying neural circuitry. These effects, which are sex-dependent and influenced by stress, may be candidates as predictors of adolescent vulnerability. A major challenge to determining if adolescents have a unique susceptibility to dependence is whether and to what extent the human data allow distinction between the increased risk due to biological immaturity, an underlying biological susceptibility to dependence, or psychosocial and environmental factors for substance dependence. Factors important to consider for development of animal models include the timing and pattern of exposure as it relates to adolescence; age of assessment, and direct comparison with similar effects following exposures to adults to demonstrate that these effects are unique to adolescence. Here we provide a roadmap for further research into what makes adolescent brain development unique. • Evidence supports increased vulnerability to drug dependence during adolescence. • A number of promising biological indicators for addiction risk are being developed. • A roadmap for further research into adolescent brain development is presented. [ABSTRACT FROM AUTHOR]